Studies with polyfunctionality substituted heterocycles: Novel syntheses of thienopyrimido-1,2,4-triazoles

Article abstract of DOI:10.1080/10426500210219

Several 3-substituted-(un)-cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-1,2,4-triazoles 10, 11, 12, 13, and 14 were prepared by reaction of an appropriate substituted 2-amino-3-cyanothiophene 1 with aliphatic acids or benzoyl chloride. Also the fusion of 1 with urea, thiourea to give the corresponding 2-oxo or thioxo-4-aminopyrimidine derivatives 6a, b and other reactions of compound 1 are reported.

Full text of DOI:10.1080/10426500210219

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Phosphorus, Sulfur, and Silicon and the Related
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Studies with Polyfunctionality Substituted
Heterocycles: Novel Syntheses of
Thienopyrimido-1,2,4-triazoles
A. B. A. El-Gazzar a , M. I. Hegab a , S. A. Swelam a & A. S. Aly a
a National Research Centre, Cairo, Egypt
Published online: 27 Oct 2010.
To cite this article: A. B. A. El-Gazzar , M. I. Hegab , S. A. Swelam & A. S. Aly (2002): Studies with Polyfunctionality
Substituted Heterocycles: Novel Syntheses of Thienopyrimido-1,2,4-triazoles, Phosphorus, Sulfur, and Silicon and the Related
Elements, 177:1, 123-136
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Phosphorus, Sulfur and Silicon, 2002, 177:123–136
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STUDIES WITH POLYFUNCTIONALITY
SUBSTITUTED HETEROCYCLES: NOVEL
SYNTHESES OF THIENOPYRIMIDO-1,2,4-TRIAZOLES
A. B. A. El-Gazzar, M. I. Hegab, S. A. Swelam, and A. S. Aly
National Research Centre, Cairo, Egypt
(Received April 10 2001.)
Several 3-substituted-(un)-cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-
1,2,4-triazoles 10, 11, 12, 13, and 14 were prepared by reaction of an ap-
propriate substituted 2-amino-3-cyanothiophene 1 with aliphatic acids
or benzoyl chloride. Also the fusion of 1 with urea, thiourea to give
the corresponding 2-oxo or thioxo-4-aminopyrimidine derivatives 6a, b
and other reactions of compound 1 are reported.
Keywords: -diketone; 1H NMR spectra; o-aminonitrile; pyrimidine;
mass spectra
The pyrimidine ring is a frequent partner in polycyclic heterocyclic
systems of biological significance.1 Compounds containing a fused
pyrimidine ring make up a broad class that has attracted attention in
the past few years owing to its wide range of biological activity. Many
potential drugs have been modelled on these compounds, particularly
4
in cancer and virus research.2 On the other hand, thienopyrimidine,
heterocyclic ring systems, have also attracted attention because of
their promising biological activities. These derivatives have analgesic,5
antipyretic,6 antianaphilactic,7,8 and antiinflammatory effects.9,10
Also, some are clinically effective antialergic,11 potentially antineo-
plastic agents,12 or have a significant hypocholesterolemic activity.13
This asset prompted us to prepare new polyheterocyclic system with
potential biological activity containing the thienopyrimidine moiety in
16
our search for new compounds of pharmacological interest.14
Syntheses of fused bi- and polycyclic compounds by annelation of a
pyrimidine ring to an existing ring are high in number and were re-
cently reviewed.11 The structure of the required starting compounds is
Address correspondence to A. B. A. El-Gazzar, National Research Centre, Cairo,
Egypt. E-mail: elgazzar2000@hotmail.com
123

124
A. B. A. El-Gazzar et al.
mainly determined by the nature of the substituents on the pyrimidine;
as a rule, systems with an amino group next to another functional
group are the most widely used.17 For this purpose the nucleophilic
character and structural diversity of amino groups have placed them
in a prominent position in synthetic chemistry. Succesive replacement
of the hydrogen atoms of the amino group with electrophilic methylene
groups, leads to the iminium salts, which can function as a Vilsmeier
or Manich reagents. This has proved to be very useful in synthetic
chemistry, especially in various one-step heterocyclization reactions.
This article reports a new method for the preparation of substituted
cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-1,2,4-triazole (10, 11) by
reaction of an appropriately substituted thiophene derivative 1 and an
acidic methylene group. The synthetic concept of constructing fused
pyrimidines from o-aminonitrile and phosegeneiminıum salts has
already been applied to the synthesis of chloroquinazolines.18
The readily available 2-amino thiophene 3-nitrile 119 was employed
as the starting material (Scheme 1). The condensation of cyclohep-
tanone with malononitrile in the presence of sulfur afforded the
2-amino-3-cyanocyclohepta(b)thiophene derivative 1 in a 87% yield.
SCHEME 1 a. triethylortho formate (acetate). Ac2O; b. methanol, ammonia
solution; c. ethoxide solution; d. formic acid, triethylortho acetate; e. formamide,
DMF; f. urea, thiourea; g. CS2, ethanolic KOH.

Substituted Heterocycles
125
Structural elucidation of compound 1 was accomplished from analytical
and spectral data. The mass spectra showed the expected molecular ion
peak and the IR spectra exhibited absorption band at = 2218 cm 1 due
to the cyano group. Formation of the desired o-aminonitrile compound 1
was also confirmed by the 1H NMR spectrum. Upon treatment with tri-
ethylorthoformate at reflux, the corresponding ethoxymethylene amino
derivative 2a was afforded in high yield.
Aminolysis of 2 (R = H) in methanol in the presence of ammo-
nium hydroxide solution yielded the aminomethylene amino deriva-
tive 3 as the intermediate structure which cyclized when refluxed
in ethanolic sodium ethoxide solution to give the cyclo-form 1-amino
cyclohepta(b)thieno[2,3-d]pyrimidine (5). The latter compound was also
prepared by the action of formamide and catalytic amount of formic
acid, 2-amino-3-cyanocyclohepta(b)thiophene (1) in refluxing dimethyl-
formamide. Also, the action of triethyortho acetate at room temperature
gave the corresponding ethoxymethylene amino derivative 2b. On the
other hand, the refluxing action on the same reaction mixture afforded
the 3-methyl cyclohepta(b)thieno[2,3-d]pyrimidine (4b) (R = CH3) as
shown in Scheme 1.
Similarly, compound 1 reacted with formic acid in presence of cat-
alytic amount of hydrochloric acid to afford the corresponding20 1,2-
dihydro-1-oxo-cyclohepta(b)thieno[2,3-d]pyrimidine (4a). The forma-
tion of 4a from compound 1 and formic acid may proceed as shown
in Scheme 2.
When compound 1 was fused with urea or thiourea at 180 C,
it gave 1-amino-3-oxo-3H-cyclohepta(b)thieno[2,3-d]pyrimidine (6a)
or the 3-thioxo derivative 6b, with compatible spectral data
(1H NMR, mass spectrum) and elemental analysis. On the
other hand, when compound 1 was heated with carbon disul-
fide in ethanolic potassium hydroxide solution, 1,3-dithioxo-1,2,3,4-
tetrahydrocyclohepta(b)thieno[2,3-d]pyrimidine (7) was obtained as
shown in Scheme 1.
The reaction of hydrazine hydrate with compound 2a in the cold
in ethanol afforded 2-amino-1-imino-1,2-dihydrocyclohepta(b)thieno
[2,3-d]pyrimidine (80), which could be rearranged to 1-hydrazino
cycloheta(b)thieno[2,3-d]pyrimidine (8). The latter compound must be
formed by the Dimroth rearrangement of intermediate 80. If the forma-
tion of amino imino (80) is faster than Dimroth rearrangement, the final
product is (80). Vice versa, if the Dimroth rearrangement of the inter-
mediate 80 is faster than the formation of amino imino 80, one ends up
with the 1-hydrazino derivative 8. Also the hydrazino derivative 8 was
prepared by the action of hydrazine hydrate with the chloro derivative
9,20 as shown in Scheme 3.

126
A. B. A. El-Gazzar et al.
SCHEME 2
The reaction of hydrazino derivative 8 with aliphatic acids
such as formic or acetic acid or acid chlorides such as benzoyl
choride afforded 3-substituted (un-)cyclohepta(b)thieno[2,3-d]pyrimido
[3,4-a]1,2,4-triazoles derivatives 10, 11, and 12, as shown in Scheme 4.
The spectral data (1H NMR, mass spectrum) and elemental analysis are
compatible with their expected structures. Also, the hydrazino deriva-
tive 8 reacted with -diketones, such as acetyl acetone, chloroacety-
lacetone and trifluroacetylacetone to form 1-(1-pyrazolyl) derivatives.
Thus, heating under reflux compound 8 with each of pentane-2,4-dione,
3-chloropentane-2,4-dione and 1,1,1-trifluropentane-2,4-dione in ab-
solute ethanol yielded 1-(3,5-dimethyl-4-(un-)substituted-1H-pyrazol-
1- yl)cyclohepta(b)thieno[2,3-d]pyrimidines 13a–c. (Scheme 3)
Reaction of
8 with diethyl oxalate at reflux yielded the
corresponding 3-ethyl cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-1,2,4-
triazole carboxylate (14), which upon saponification was converted

SCHEME 3
SCHEME 4
127

128
A. B. A. El-Gazzar et al.
to the 3-(cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-1,2,4-triazole) car-
1
boxylic (15). The IR spectra showed absorption bands at 3450 cm
(OH), and 1690 (CO). The 1H NMR showed the signal for the hydroxyl
group at 10.23 ppm. The reaction mechanism may proceed as shown in
Scheme 5.
SCHEME 5
CONCLUSION
The prepared compounds seem to be interesting for biological activity
studies. Furthermore, the present investigation offers rapid and effec-
tive new procedures for the synthesis of the title ring systems.
EXPERIMENTAL
All melting points are uncorrected. The 1H NMR spectra were recorded
on Bruker (WM-250 MHz), Bruker (AC-250 MHz) spectrometers (Fac-
ulty of Chemistry, Konstantz University, Germany), and a Varian 1H

Substituted Heterocycles
129
Gemini 200 spectrometer (National Research Centre, Egypt) and chem-
ical shifts were expressed as values against TMS as internal stan-
dards. IR spectra were recorded as KBr pellets on a Perkin-Elmer 1430
spectrometer, (National Research Centre and Department of Chemistry,
Cairo University). Mass spectra were recorded on GCMS-QP 1000 Ex
Shimadzu Japan (Gas Chromatography-Mass Spectromer). Microan-
alytical data were performed by the Microanalytical Centre at Cairo
University and National Research Centre (Egypt). All compounds gave
satisfactory C, H, N, and S analysis (Table I).
TABLE I Physical Data for the Products 2–15
Elemental analyses calcd./found
Comp. no.
m.p. C
Yield %
81
M. F. (m. wt.)
C
H
N
2a
115–118
decom.
81–83
C13H16N2OS
(248.34)
62.87
62.76
64.09
64.13
60.24
60.31
59.97
60.02
61.51
61.49
60.24
60.19
56.15
56.20
52.56
52.63
49.22
49.20
58.99
59.02
60.44
60.47
67.47
67.51
64.40
64.43
57.73
57.81
54.53
54.61
56.95
57.07
54.15
54.18
6.49
6.51
6.91
6.81
5.97
5.93
5.49
5.42
6.02
5.98
5.97
5.96
5.57
5.48
5.21
5.81
4.51
4.53
4.95
4.89
5.46
5.49
5.03
4.98
6.08
6.09
5.15
5.13
4.29
4.32
5.10
5.11
4.20
4.23
11.28
11.31
10.68
10.73
19.16
19.21
12.72
12.63
11.96
12.01
19.16
19.17
17.86
17.93
16.72
16.83
10.44
10.39
22.93
23.01
21.69
21.61
17.49
17.47
18.78
18.84
16.83
16.77
15.90
15.87
17.71
17.83
19.43
19.37
2b
3a
4a
4b
5a
6a
6b
7
83
73
67
68
49
63
59
63
87
75
69
81
73
82
53
61
C
14H18N2OS
(262.36)
melted
137–139
decom.
224–226
decom.
187–188
decom.
231–233
decom.
214–216
decom.
271–73
decom.
234–236
decom.
151–153
decom.
217–219
decom.
269–271
decom.
163–165
melted
C
11H13N3S
(219.29)
C11H12N2OS
(220.29)
C
12H14N2OS
(234.31)
C11H13N3S
(219.29)
C
11H13N3OS
(235.29)
C
11H13N3S2
(251.35)
C11H12N2S3
(268.42)
10
C
12H12N4S
(244.31)
11
C
13H14N4S
(258.33)
12
C18H16N4S
(320.40)
C16H18N4S
(298.39)
13a
13b
13c
14
138–141
melted
151–153
melted
206–209
decom.
273–275
decom.
C16H17ClN4S
(332.84)
C16H15F3N4S
(352.37)
C15H16N4O2S
(316.33)
15
C
13H12N4O2S
(288.29)

130
A. B. A. El-Gazzar et al.
2-Ethoxymethylene amino-3-cyanocyclohepta(b)-
thiophene (2a)
A mixture of compound 1 (1.90 g, 10 mmol) and triethyl orthoformate
(2.96 g, 20 mmol) was stirred under reflux in acetic anhydride (30 ml)
for 6 h. The reaction mixture was allowed to cool to room temperature,
poured into cold water (100 ml), and neutralized by ammonia solution.
The deposited coprecipitate was collected by filtration, washed by wa-
ter, dried, and crystallized from ethanol in 81% yield, m.p. 115–118 C;
1H NMR (CDCl3) ppm: 1.31 (t, 3H, CH3), 1.60 (m, 4H, 2 CH2), 1.75
(m, 2H, CH2), 2.68 (m, 2H, CH2), 3.48 (m, 2H, CH2), 3.79 (q, 2H, CH2),
9.18 (s, H, methylenic proton); MS (EI): m/z: 248 (M+), 249 (MH+),
234 (MH CH3).
2-Ethoxy-2-methylmethylene
amino-3-cyanocyclohepta(b)thiophene (2b)
A mixture of compound 1 (1.90 g, 10 mmol) and triethyl orthoacetate
(5 ml) was stirred at room temperature for 13 h. The excess solvent
was evaporated under reduced pressure. The solid formed was collected
and crystallized from cyclohexane in 83% yield, m.p. 81–83 C; 1H NMR
(CDCl3) ppm: 1.30 (t, 3H, CH3), 1.70 (m, 4H, 2 CH2), 1.87 (m, 2H,
CH2), 2.05 (s, 3H, CH3), 2.75 (m, 2H, CH2), 4.30 (q, 2H, CH2); MS (EI):
m/z: 261 (M H), 248 (M CH4), 234 (M C2H7).
2-Aminomethylene amino-3-cyanocyclohepta (b)-
thiophene (3a)
A mixture of compound 2a (2.48 g, 10 mmol) and ammonia solution
30–40% (20 ml) was stirred under reflux in methanol (50 ml) for 10 h.
The reaction mixture was allowed to cool to room temperature, poured
into cold water (100 ml), and neutralized by the addition of acetic acid.
The deposited coprecipitate was filtered off, washed with water, dried,
1
and crystallized from ethanol in 73% yield, m.p. 137–139 C (dec.), H
NMR (CDCl3) ppm: 1.58 (m, 4H, 2 CH2), 1.78 (m, 2H, CH2), 2.69 (m,
2H, CH2), 3.35 (m, 2H, CH2), 7.40 (s, H, CH), 8.35 (br. s, NH).
1,2-Dihydro-1-oxo-cyclohepta(b)thieno[2,3-d]-
pyrimidine (4a)
A mixture of compound 1 (1.90 g, 10 mmol), formic acid (10 ml) and cat-
alytic amount of concentrated hydrochloric acid was heated under reflux
for 12 h; the reaction mixture was allowed to cool to room temperature
and poured into cold water (100 ml). The formed solid was collected

Substituted Heterocycles
131
by filtration, washed by ethanol (20 ml), dried, and crystallized from
DMF/ethanol (2:1) in 67% yield, m.p. 224–226 C (lit.,20 220–222 C); 1H
NMR (DMSO-d6) ppm: 1.60 (m, 4H, 2 CH2), 1.85 (m, 2H, CH2), 2.85
(m, 2H, CH2), 3.30 (m, 2H, CH2), 8.05 (s, H, pyrimidine proton), 12.35
(br. s, NH, exchangeable with D2O); MS (EI): m/z: 221 (MH+), 220 (M+),
205 (MH+ O).
1,2-Dihydro-3-methyl-1-oxo-cyclohepta(b)thieno-
[2,3-d] pyrimidine (4b)
A mixture of compound 1 (1.90 g, 10 mmol) and triethyl orthoacetate
(5 ml) was stirred under reflux for 10 h; the reaction mixture was al-
lowed to cool to room temperature and poured into cold water (100 ml).
The deposited coprecipitate was collected by filtration, washed by
water, dried, and crystallized from DMF/ethanol (2:1) in 68% yield,
m.p. 187–188 C; 1H NMR (DMSO-d6) ppm: 1.55 (m, 4H, 2 CH2), 1.75
(m, 2H, CH2), 2.13 (s, 3H, CH3), 2.62 (m, 2H, CH2), 3.35 (m, 2H, CH2),
11.40 (br. s, NH, exchangeable with D2O); MS (EI): m/z: 234 (M+), 220
(MH+ CH3).
1,2-Dihydro-1-aminocyclohepta(b)thieno[2,3-d]-
pyrimidine (5a)
Method A: To a warmed ethanolic sodium ethoxide solution (0.23 g,
10 mmol sodium metal in 50 ml absolute ethanol), 2.19 g, 10 mmol of
compound 3a was added. The mixture was stirred under reflux for 5 h.
The reaction mixture was allowed to cool to room temperature, poured
into cold water (100 ml), and neutralized by the addition of acetic acid.
The solid formed was filtered off, dried, and crystallized from DMF in
49% yield, m.p. 231–233 C (dec.).
Method B: A mixture of compound 1 (1.90 g, 10 mmol), formamide
(0.45 g, 10 mmol) and formic acid (2 ml) was stirred under reflux in
dimethylformamide (20 ml) for 9 h; the reaction mixture was allowed
to cool, poured in water (100 ml), and neutralized by ammonia solution.
The deposite coprecipitate was collected, washed by water, ethanol,
dried, and crystallized from DMF/ethanol (2:1) in 75% yield, m.p.
1
232–234 C; H NMR (DMSO-d6) ppm: 1.57 (m, 4H, 2 CH2), 1.78 (m,
2H, CH2), 2.71 (m, 2H, CH2), 3.37 (m, 2H, CH2), 8.08 (S, H, pyrimidine
proton).
1-Amino-3-oxo or (thioxo)-3H-cyclohepta(b)-
thieno[2,3-d]pyrimidine (6a,b)
General procedure: A mixture of compound 1 (1.90 g, 10 mmol) and
urea or thiourea (10 mmol) was heated at 180 C in a test tube on sand

132
A. B. A. El-Gazzar et al.
bath for 4 h. The mixture was allowed to cool to room temperature;
the product was solidified by cooling and addition of methanol (50 ml).
The precipitate formed was collected by filtration and crystallized from
the proper solvent to produce 6a,b.
1-Amino-3-oxo-3H-cyclohepta(b)thieno[2,3-d]-
pyrimidine (6a)
From compound 1 (1.90 g, 10 mmol) and urea (0.61 g, 10 mmol). The
compound was obtained as white crystals, crystallized from dioxane in
1
63% yield, m.p. 214–216 C; H NMR (DMSO-d6) ppm: 1.93 (m, 4H,
2 CH2), 2.85 (m, 2H, CH2), 3.00 (m, 2H, CH2), 3.32 (m, 2H, CH2), 3.89
(br. s, NH), 10.22 (br. s, NH).
1-Amino-3-thioxo-3H-cyclohepta(b)thieno[2,3-d]-
pyrimidine (6b)
From compound 1 (1.90 g, 10 mmol) and thiourea (0.77 g, 10 mmol).
The compound was obtained as yellow crystals, crystallized from
dioxane in 59% yield, m.p. 271–273 C; 1H NMR (DMSO-d6) ppm:
1.56 (m, 4H, 2 CH2), 1.80 (m, 2H, CH2) 2.75 (m, 2H, CH2), 3.12 (m,
2H, CH2), 3.50 (br. s, NH), 3.61 (br. s, NH).
1,3-Dithioxo-1,2,3,4-tetrahydrocyclohepta(b)-
thieno[2,3-d]pyrimidine (7)
To a warmed potassium hydroxide solution (prepared by dissolving
0.56 g, 10 mmol of potassium hydroxide in 50 ml ethanol), 1.90 g, 10
mmol of compound 1 was added and excess carbon disulfide (10 ml). The
mixture was heated on water bath at 80 C under reflux for 10 h, then
allowed to cool to room temperature, poured into cold water (100 ml),
and neutralized with diluted acetic acid. The deposited coprecipitate
was collected by filtration, washed with water, dried and crystallized
1
from DMF/ethanol (2:1) in 63% yield, m.p. 234–236 C (dec.); H NMR
(DMSO-d6) ppm: 1.55 (m, 4H, 2 CH2), 1.77 (m, 2H, CH2), 2.75 (m,
2H, CH2), 3.60 (m, 2H, CH2), 13.22 (br. s, NH, exchangeable with D2O),
13.90 (br. S, NH, exchangeable with D2O).
1-Chloro cyclohepta(b)thieno[2,3-d]pyrimidine (9)
A solution of compound 4a (2.20 g, 10 mmol) in dry dioxane (30 ml) was
treated with phosphorus oxychloride (7 ml) and the mixture was stirred
under reflux for 3 h. The reaction mixture was allowed to cool to room
temperature and poured into ice-water (200 g), whereby a solid was

Substituted Heterocycles
133
separated, filtered off, and crystallized from petroleum ether in 71%
yield, m.p. 68–71 C (dec.) (lit.,20 65–67 C).
1-Hydrazino cyclohepta(b)thieno[2,3-d]pyrimidine (8)
Method A: A mixture of compound 2a (2.45 g, 10 mmol) and hydrazine
hydrate 80% (7.5 ml) in ethanol (50 ml) was heated at 50 C for 3 h.
The reaction mixture was allowed to cool to room temperature. The
deposited so-precipitate was filtered off and crystallized from dioxane
in 83% yield, m.p. 195–197 C (dec.) (lit.,20 193–194 C).
Method B: A mixture of compound 9 (2.38 g, 10 mmol) and hydrazine
hydrate 80% (7.5 ml) was stirred under reflux in dry dioxane (30 ml) for
5 h. The reaction mixture was allowed to cool to 0 C for 5 h. The solid
was collected by filtration and crystallized from dioxane/ethanol (2:1)
in 79% yield, as same as that of which produced by Method A. 1H NMR
(DMSO-d6) ppm: 1.62 (m, 4H, 2 CH2), 1.82 (m, 2H, CH2), 2.28 (m, 2H,
CH2), 2.64 (m, 2H, CH2), 4.51 (br. s, 2H, NH2, exchangeable with D2O),
7.31 (s, H, pyrimidine proton), 8.70 (br. s, NH, exchangeable with D2O);
MS (EI): m/z: 234 (M+), 221 (MH+ NH2).
3H-Cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-
1,2,4-triazole (10)
A mixture of compound 8 (2.34 g, 10 mmol), formic acid (10 ml), and a
catalytic amount of concentrated hydrochloric acid was heated under
reflux for 7 h. The reaction mixture was allowed to cool to room temper-
ature and poured into water (200 ml). The precipitate that was formed
was collected by filtration, washed with ethanol (50 ml), dried, and crys-
tallized from dioxane/ethanol (2:1) in 87% yield, m.p. 151–153 C (dec.)
1
(lit.,20 153 C); H NMR (DMSO-d6) ppm: 1.89 (m, 4H, 2 CH2), 2.78
(m, 2H, CH2), 3.00 (m, 2H, CH2), 3.72 (m, 2H, CH2), 8.37 (s, H, triazole
proton), 8.39 (s, H, pyrimidine proton).
3-Methyl-cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-
1,2,4-triazole (11)
A mixture of compound 8 (2.34 g, 10 mmol), glacial acetic acid (30 ml),
was heated under reflux for 15 h; the reaction mixture was allowed to
cool to room temperature and poured into water (200 ml). The solid
so-formed was collected by filtration, dried, and crystallized from acetic
acid in 75% yield, m.p. 217–219 C; 1H NMR (DMSO-d6) ppm: 1.91 (m,
4H, 2 CH2), 2.86 (m, 2H, CH2), 3.02 (m, 2H, CH2), 3.14 (m, 2H, CH2),
3.74 (s, 3H, CH3), 8.41 (s, H, pyrimidine proton).

134
A. B. A. El-Gazzar et al.
3-Phenyl-cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-
1,2,4-triazole (12)
A mixture of compound 8 (2.34 g, 10 mmol), benzoyl chloride (30 ml),
was stirred under reflux for 8 h. The reaction mixture was allowed to
cool to room temperature and poured into water (200 ml). The solid
formed was filtered off, dried, and crystallized from dioxane/ethanol
1
(2:1) in 69% yield, m.p. 269–271 C (dec.); H NMR (DMSO-d6) ppm:
1.60 (m, 4H, 2CH2), 1.80 (m, 2H, CH2), 2.70 (m, 2H, CH2), 2.85 (m,
2H, CH2), 7.40–7.63 (m, 5H, phenyl protons), 7.95 (s, H, pyrimidine
proton); MS (EI): m/z: 320 (M+), 243 (M+ C6H5).
1-(3,5-Dimethyl-4-(un)substituted-1H-pyrazol-1-yl)-
cyclohepta(b)thieno-[2,3-d]pyrimidine (13a–c)
General procedure: A mixture of compound 8 (2.34 g, 10 mmol) and
-diketone (10 mmol) in absolute ethanol (30 ml) was stirred under
reflux for 5 h. The reaction mixture was allowed to cool to 0 C for 3 h.
The deposited coprecipitate was filtered off, dried, and crystallized from
appropriate solvent to produce 13a–c in high yield.
1-(3,5-Dimethyl-4H-pyrazol-1-yl)cyclohepta(b)-
thieno[2,3-d]pyrimidine (13a)
From compound 8 (2.34 g, 10 mmol) and pentan-2,4-dione (1.00 g,
10 mmol). The compound was obtained as colorless crystals, crystal-
lized from dioxane in 81% yield, m.p. 163–165 C; IR: 1H NMR (CDCl3)
ppm: 1.86 (m, 4H, 2 CH2), 1.95 (m, 2H, CH2), 2.28 (s, 3H, CH3), 2.32
(s, 3H, CH3), 2.68 (m, 2H, CH2), 3.06 (m, 2H, CH2), 6.01 (s, H, pyrazole
proton), 8.73 (s, H, pyrimidine proton).
1-(3,5-Dimethyl-4-chloropyrazol-1-yl)-
cyclohepta(b)thieno[2,3-d]pyrimidine (13b)
From compound 8 (2.34 g, 10 mmol) and 3-chloro-2,4-pentandione
(1.34 g, 10 mmol). The compound was obtained as white crystals, crys-
1
tallized from dioxane/ethanol (1:1) in 73% yield, m.p. 138–141 C; H
NMR (CDCl3) ppm: 1.83 (m, 4H, 2 CH2), 1.85 (m, 2H, CH2), 2.11 (s,
3H, CH3), 2.72 (m, 2H, CH2), 2.99 (m, 2H, CH2), 3.55 (s, 3H, CH3), 8.32
(s, H, pyrimidine proton).
1-(3-Methyl-4H-trifluromethylpyrazol-1-yl)-
cyclohepta(b)thieno[2,3-d]pyrimidine (13c)
From compound 8 (2.34 g, 10 mmol) and 1,1,1-trifluro-2,4-pentandione
(1.54 g, 10 mmol). The compound was obtained as colorless crystals,

Substituted Heterocycles
135
crystallized from ethanol in 82% yield, m.p. 151–153 C; 1H NMR
(CDCl3) ppm: 1.83 (m, 4H, 2 CH2), 1.85 (m, 2H, CH2), 2.23 (s, 3H,
CH3), 2.66 (m, 2H, CH2), 3.00 (m, 2H, CH2), 5.99 (s, H, pyrazolo pro-
ton), 8.39 (s, H, pyrimidine proton).
3-Ethyl-(cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-
1,2,4-triazole)carboxylate (14)
A mixture of compound 8 (2.34 g, 10 mmol), diethyloxalate (10 ml) was
heated under reflux for 18 h. The reaction mixture was allowed was to
cool to room temperature and poured into cold water (100 ml). The solid
formed was filtered off, dried, and crystallized from ethanol (50 ml) in
1
53% yield, m.p. 206–209 C; H NMR (DMSO-d6) ppm: 1.20 (t, 3H,
CH3), 1.88 (m, 4H, 2CH2), 1.92 (m, 2H, CH2), 2.29 (m, 2H, CH2), 3.19
(m, 2H, CH2), 4.18 (q, 2H, CH2), 7.78 (s, H, pyrimidine proton).
3-(cyclohepta(b)thieno[2,3-d]pyrimido[3,4-a]-
1,2,4-triazole) Carboxylicacid (15)
A stirred suspension of compound 13 (2.88 g, 10 mmol) in 5% of sodium
hydroxide (3 ml) was stirred under reflux for 45 min. The cold mixture
was acidified to pH 5–6 with dilute hydrochloric acid and the white
precipitate was filtered off, washed with water, dried, and crystallized
from dioxane/ethanol (1:1) in 61% yield, m.p. 273–275 C (dec.); 1H NMR
(DMSO-d6) ppm: 1.91 (m, 4H, 2CH2), 2.78 (m, 2H, CH2), 2.92 (m, 2H,
CH2), 3.56 (m, 2H, CH2), 8.37 (s, H, pyrimidine proton), 10.23 (br. s,
OH); MS (EI): m/z: 289 (MH+), 243 (MH+ COOH).
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